ABSTRACT Obesity and type 2 diabetes (T2D) occur disproportionately among African-American (AA) women. The neuroendocrine system, and in particular the hypothalamic-pituitary-adrenal (HPA) axis, plays a key role in the homeostasis of body weight through regulation of energy intake and expenditure. Perinatal events may cause changes in leptin and insulin levels that lead to altered hypothalamic development and lasting effects on body weight regulation and glucose homeostasis. Chronic stressors can cause deregulation of both the HPA axis and the sympathetic adrenal medullary axis, increasing the risk of developing metabolic diseases such as obesity and T2D. Relative to U.S. white women, AA women have a higher exposure to factors that can unfavorably alter functioning of the neuroendocrine system. Specifically, AA women are less likely to have been breastfed, more likely to have been born preterm and with a low birth weight, and more likely to experience violence victimization, racism, depression, and sleep deprivation. Because the FTO gene, the gene most strongly associated with fat mass and obesity in AA as well as European ancestry populations, is highly expressed in the central nervous system and hypothalamus and is involved in food intake regulation, genetic variants of the FTO gene may characterize individuals who are more susceptible to obesity or T2D under conditions that affect neuroendocrine functioning. We propose to prospectively assess whether the above- mentioned factors are associated with weight gain and incidence of T2D in AA women, and whether genetic variants in the FTO gene modify these associations. Our study will be based on the Black Women's Health Study (BWHS), an ongoing cohort study of 59,000 AA women with a wealth of prospectively collected data and with stored DNA samples. The BWHS has collected information on weight every two years during follow-up since baseline in 1995, and over 6,000 incident cases of T2D have occurred through 2009. We have already published on the relation of body mass index, dietary factors, and physical activity to risk of T2D and have also reported positive associations of racism and low socioeconomic status with weight gain in the BWHS. The proposed study will provide novel data on factors that may be contributing to the epidemic of obesity and T2D in AA women and in other population groups as well.